Pharmacological therapy utilizing pure formulations of S(-) amlodipine results in effective theraputic results while avoiding toxicities and adverse effects of racemic amlodipine. The methods and compositions described include the enriched deuterated forms of amlodipine as well as the nonenriched form. Amlodipine and deuteroamlodipine have a chiral center at C4 in the dihydropyridine ring, and thus can exist as optical isomers. The isomers may be separated by various methods, for example selective crystallization and column chromatography. See for example T. Shibanuma, et al., Chem. Pharm. Bull., 28, 2809-2812 (1980). Alternatively, S(-) amlodipine may be prepared using optically active reactants, or by a combination of separation and chiral synthesis. Optical isomers of compounds are specified (+) or (-), indicating the direction the chiral center rotates a plane of polarized light.
Optically active amlodipine, amlodipine derivatives and salts and deuterated amlodipine or deuterated amlodipine derivatives and salts are designated herein using the IUPAC R-S convention, sometimes called the "sequence rule." A description of the R-S convention may be found, for example, in "Introduction to Organic Chemistry" by A. Streitwieser, Jr. and C. Heathcock, (Macmillan Pub. Co., New York, 1976), pages 110-114.
Optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been thought to be a potent teratogen.
The active compound of the present invention is the S(-) isomer of the compound amlodipine and the s(-) isomer of deuterated amlodipine. Amlodipine is described in U.S. Pat. No. 4,572,909. Chemically, this compound is the S(-) isomer of amlodipine and is a long-acting calcium channel blocker.
Amlodipine is chemically described as (R.S.) 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6- methyl-3,5-pyridinedicarboxylate. Its empirical formula is: C.sub.2 OH.sub.25 ClN.sub.2 O.sub.5. Also encompassed within the present invention are compositions and methods of using deuterated compounds which are related to amlodipine. In the structures given below, R represents either hydrogen or deuterium. In a preferred embodiment, R.sup.1 represents either hydrogen or deuterium wherein one or more R.sup.1 is deuterium. The symbol "*" denotes the chiral carbon. ##STR1##
The present commercial formulation of amlodipine contains the drug as the salt; amlodipine besylate. The term "amlodipine" herein refers to amlodipine and its pharmaceutically suitable salts and esters including amlodipine besylate and deuterated amlodipine and its pharmaceutically acceptable salts and esters including deuterated amlodipine besylate. This isomer will hereinafter be referred to as S(-) amlodipine. The terms "S(-) amlodipine" and "S(-) isomer of amlodipine" as used herein includes substantially optically pure S(-) amlodipine as well as optically pure S(-) amlodipine.